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Clinical Trial Results:
A Phase 1/2, Open-Label, Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Patients With Metastatic or Locally Advanced Solid Tumors, With Expansion to Second-Line Cervical Cancer

Summary
EudraCT number	2017-000556-26
Trial protocol	FR EE ES BE LT PL
Global end of trial date	15 Jun 2022

Results information
Results version number	v1(current)
This version publication date	30 Jun 2023
First version publication date	30 Jun 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

C-700-01

ISRCTN number

US NCT number

NCT03104699

WHO universal trial number (UTN)

Sponsor organisation name

Agenus, Inc.

Sponsor organisation address

3 Forbes Road, Lexington, MA, United States, 02421

Public contact

Amy Cohen, Agenus, Inc., 1 781.674.4615, AGEN2034@agenusbio.com

Scientific contact

Amy Cohen, Agenus, Inc., 1 781.674.4615, AGEN2034@agenusbio.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

15 Jun 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Jun 2022

Was the trial ended prematurely?

Main objective of the trial

The main objectives of this trial were to assess the safety and tolerability of balstilimab (AGEN2034), determine the maximum tolerated dose of balstilimab in participants with metastatic or locally advanced solid tumours (Phase 1 safety cohort), and to assess the best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in participants with recurrent, unresectable, or metastatic cervical cancer that had progressed after a platinum doublet administered for treatment of advanced disease (Phase 2 efficacy expansion cohort).

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Apr 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 65

Country: Number of subjects enrolled

Brazil: 21

Country: Number of subjects enrolled

Chile: 19

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Poland: 4

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Estonia: 3

Country: Number of subjects enrolled

France: 81

Worldwide total number of subjects

211

EEA total number of subjects

102

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

154

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

For Phase 1 results, at the time of data cut off, 2 participants who completed 24 months of treatment were ongoing in follow up. Phase 1 subject disposition will be updated as soon as data becomes available.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1: Dose 1

Arm description

Participants received 1 milligram/kilogram every 2 weeks balstilimab for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Balstilimab

Investigational medicinal product code

Other name

AGEN2034, Anti-PD-1

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Balstilimab infusions were administered within 60 minutes (-10/+20 minutes) using an infusion pump.

Phase 1: Dose 2

Arm description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Balstilimab

Investigational medicinal product code

Other name

AGEN2034, Anti-PD-1

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Balstilimab infusions were administered within 60 minutes (-10/+20 minutes) using an infusion pump.

Phase 1: Dose 3

Arm description

Participants received 6 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Balstilimab

Investigational medicinal product code

Other name

AGEN2034, Anti-PD-1

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Balstilimab infusions were administered within 60 minutes (-10/+20 minutes) using an infusion pump.

Phase 1: Dose 4

Arm description

Participants received 10 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Balstilimab

Investigational medicinal product code

Other name

AGEN2034, Anti-PD-1

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Balstilimab infusions were administered within 60 minutes (-10/+20 minutes) using an infusion pump.

Phase 1: Dose 5

Arm description

Participants received 10 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Balstilimab

Investigational medicinal product code

Other name

AGEN2034, Anti-PD-1

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Balstilimab infusions were administered within 60 minutes (-10/+20 minutes) using an infusion pump.

Phase 2: Recommended Phase 2 Dose

Arm description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for a maximum of 24 months or until progression, unacceptable toxicity, stopping the study drug, or withdrawal from the study.

Arm type

Experimental

Investigational medicinal product name

Balstilimab

Investigational medicinal product code

Other name

AGEN2034, Anti-PD-1

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Balstilimab infusions were administered within 60 minutes (-10/+20 minutes) using an infusion pump.

Number of subjects in period 1	Phase 1: Dose 1	Phase 1: Dose 2	Phase 1: Dose 3	Phase 1: Dose 4	Phase 1: Dose 5	Phase 2: Recommended Phase 2 Dose
Started	10	10	10	10	10	161
Received at Least 1 Dose of Study Drug	10	10	10	10	10	161
Completed	0	0	0	0	0	28
Not completed	10	10	10	10	10	133
Consent withdrawn by subject	2	2	4	8	4	6
Physician decision	-	-	2	1	-	-
Death	6	3	-	1	1	107
Participant left to participate in another trial	-	-	-	-	-	1
Administrative study closure	-	-	-	-	-	13
Completed Follow Up	2	2	1	-	2	-
Lost to follow-up	-	1	1	-	-	5
Progressive disease	-	-	-	-	1	1
Still in study	-	-	2	-	-	-
Disease Progression	-	2	-	-	-	-
Protocol deviation	-	-	-	-	2	-

Baseline characteristics

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Reporting group title

Phase 1: Dose 1

Reporting group description

Participants received 1 milligram/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 2

Reporting group description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 3

Reporting group description

Participants received 6 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 4

Reporting group description

Participants received 10 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 5

Reporting group description

Participants received 10 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Reporting group title

Phase 2: Recommended Phase 2 Dose

Reporting group description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for a maximum of 24 months or until progression, unacceptable toxicity, stopping the study drug, or withdrawal from the study.

Reporting group values	Phase 1: Dose 1	Phase 1: Dose 2	Phase 1: Dose 3	Phase 1: Dose 4	Phase 1: Dose 5	Phase 2: Recommended Phase 2 Dose	Total
Number of subjects	10	10	10	10	10	161	211
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	7	9	6	7	6	119	154
From 65-84 years	3	1	4	3	4	42	57
85 years and over	0	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	8	8	9	9	8	161	203
Male	2	2	1	1	2	0	8
Race
Units: Subjects
Asian	0	3	1	1	1	1	7
Black or African American	2	1	0	0	0	2	5
White	8	6	9	9	9	72	113
Not Reported (France)	0	0	0	0	0	81	81
Romanian	0	0	0	0	0	1	1
Mixed	0	0	0	0	0	3	3
Brown	0	0	0	0	0	1	1
Ethnicity
Units: Subjects
Hispanic or Latino	1	0	2	1	1	38	43
Not Hispanic or Latino	9	10	8	9	9	39	84
Unknown	0	0	0	0	0	82	82
Not Reported	0	0	0	0	0	2	2

End points

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Reporting group title

Phase 1: Dose 1

Reporting group description

Participants received 1 milligram/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 2

Reporting group description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 3

Reporting group description

Participants received 6 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 4

Reporting group description

Participants received 10 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 5

Reporting group description

Participants received 10 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Reporting group title

Phase 2: Recommended Phase 2 Dose

Reporting group description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for a maximum of 24 months or until progression, unacceptable toxicity, stopping the study drug, or withdrawal from the study.

Subject analysis set title

Phase 1: All

Subject analysis set type

Full analysis

Subject analysis set description

All participants that received balstilimab for up to 24 months during Phase 1.

Subject analysis set title

Intent-to-treat Efficacy Analysis Set (ITT EAS)

Subject analysis set type

Intention-to-treat

Subject analysis set description

All participants who received ≥1 dose of study treatment, with measurable disease at baseline (per Independent Endpoint Review Committee [IERC]).

Subject analysis set title

Dose-limiting Toxicity (DLT) Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants who were enrolled for DLT evaluation (excluding participants enrolled to backfill cohorts) and either received all study treatment administrations or stopped treatment due to a DLT during the DLT evaluation period.

Subject analysis set title

Receptor Occupancy Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants who completed ≥1 infusion of study drug, with adequate measurements of programmed cell death protien-1 (PD-1) receptor occupancy on circulating T cells.

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

All participants who received ≥1 dose of study treatment.

Subject analysis set title

Pharmacokinetic (PK) Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants who completed ≥1 infusion of study drug and who had sufficient evaluable drug concentration measurements prior to and after treatment.

Primary: Phase 1: Number of Participants Experiencing DLTs for Balstilimab

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End point title

Phase 1: Number of Participants Experiencing DLTs for Balstilimab ^[1]

End point description

A DLT was defined as any treatment-related toxicity that was National Cancer Institute Common Terminology Criteria for Adverse Event Grade ≥3, confirmed by the safety monitoring committee to be relevant for the study drug treatment, and that occurred during the first 3 weeks of balstilimab treatment in the dose escalation portion of the study (DLT evaluation period).

End point type

Primary

End point timeframe

21 Days

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only the number of participants is reported for this end point.

End point values	Dose-limiting Toxicity (DLT) Analysis Set
Number of subjects analysed	18
Units: Participants	0

No statistical analyses for this end point

Primary: Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)

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End point title

Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) ^[2]

End point description

An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which did not necessarily have a causal relationship with the treatment. TEAEs were AEs with onset dates during the on-treatment period, or the worsening of an event during the on-treatment period.

End point type

Primary

End point timeframe

From the time of the first dose to the end of follow-up (up to 2 years after the last dose)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only the number of participants is reported for this end point.

End point values	Phase 1: All
Number of subjects analysed	50 ^[3]
Units: Participants	50

Notes
[3] - Safety Analysis Set

No statistical analyses for this end point

Primary: Phase 2: Objective Response Rate (ORR)

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End point title

Phase 2: Objective Response Rate (ORR) ^[4] ^[5]

End point description

ORR was defined as proportion of participants with a BOR of complete response (CR) or partial response (PR), as determined by an IERC per RECIST 1.1.

End point type

Primary

End point timeframe

Up to 4 years

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only percentage and confidence interval are reported for this end point.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only percentage and confidence interval are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	160 ^[6]
Units: Percentage of participants
number (confidence interval 95%)	15.6 (10.8 to 22.0)

Notes
[6] - ITT EAS

No statistical analyses for this end point

Secondary: Phase 1: Receptor Occupancy of Circulating T Cells

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End point title

Phase 1: Receptor Occupancy of Circulating T Cells

End point description

The percentage of PD-1 receptor occupancy on circulating T cells was measured as an indication of target engagement.

End point type

Secondary

End point timeframe

4 hours after the first dose (Cycle 1 Day 1) and immediately prior to the second dose (Cycle 2 Day 1)

End point values	Receptor Occupancy Analysis Set
Number of subjects analysed	18 ^[7]
Units: Percent occupancy
arithmetic mean (standard deviation)
Cycle 1 Day 1	72.7 ( 9.48 )
Cycle 2 Day 1	67.4 ( 13.89 )

Notes
[7] - Cycle 1 Day 1 (N=18); Cycle 2 Day 1 (N=16)

No statistical analyses for this end point

Secondary: Phase 1: Maximum Drug Concentration Observed Postdose (Cmax)

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End point title

Phase 1: Maximum Drug Concentration Observed Postdose (Cmax) ^[8]

End point description

Blood samples were collected for serum balstilimab concentration determinations. Results are reported as micrograms/millilitre (ug/mL).

End point type

Secondary

End point timeframe

Pre-dose through 3 months after last dose

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the geometric mean and coefficient of variation are reported for the participants in Phase 1.

End point values	Phase 1: Dose 1	Phase 1: Dose 2	Phase 1: Dose 3	Phase 1: Dose 4	Phase 1: Dose 5
Number of subjects analysed	10 ^[9]	9 ^[10]	10 ^[11]	10 ^[12]	10 ^[13]
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	18.1 ( 34.3 )	71.9 ( 19.5 )	153 ( 23.7 )	236 ( 26.6 )	282 ( 28.4 )
Cycle 2 Day 1	20.3 ( 47.0 )	86.3 ( 30.0 )	161 ( 27.5 )	239 ( 28.2 )	315 ( 25.5 )

Notes
[9] - PK Analysis Set
[10] - PK Analysis Set
[11] - PK Analysis Set; Cycle 1 Day 1 (N=10); Cycle 2 Day 1 (N=8)
[12] - PK Analysis Set; Cycle 1 Day 1 (N=9); Cycle 2 Day 1 (N=10)
[13] - PK Analysis Set; Cycle 1 Day 1 (N=10); Cycle 2 Day 1 (N=7)

No statistical analyses for this end point

Secondary: Phase 1: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last)

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End point title

Phase 1: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last) ^[14]

End point description

Blood samples were collected for serum balstilimab concentration determinations. Results are reported as hours*micrograms/millilitre (h*µg/mL).

End point type

Secondary

End point timeframe

Pre-dose through 3 months after last dose

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the geometric mean and coefficient of variation are reported for the participants in Phase 1.

End point values	Phase 1: Dose 1	Phase 1: Dose 2	Phase 1: Dose 3	Phase 1: Dose 4	Phase 1: Dose 5
Number of subjects analysed	10 ^[15]	9 ^[16]	10 ^[17]	10 ^[18]	10 ^[19]
Units: h*ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	1265 ( 47.4 )	6470 ( 34.6 )	12632 ( 51.5 )	22294 ( 47.5 )	30751 ( 50.4 )
Cycle 2 Day 1	1477 ( 73.7 )	7725 ( 40.2 )	17479 ( 49.4 )	21298 ( 47.1 )	42266 ( 41.0 )

Notes
[15] - PK Analysis Set
[16] - PK Analysis Set
[17] - PK Analysis Set; Cycle 1 Day 1 (N=10); Cycle 2 Day 1 (N=8)
[18] - PK Analysis Set; Cycle 1 Day 1 (N=9); Cycle 2 Day 1 (N=10)
[19] - PK Analysis Set; Cycle 1 Day 1 (N=10); Cycle 2 Day 1 (N=7)

No statistical analyses for this end point

Secondary: Part 1: Number of Participants with Serum Anti-drug Antibodies (ADAs) for Balstilimab

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End point title

Part 1: Number of Participants with Serum Anti-drug Antibodies (ADAs) for Balstilimab ^[20]

End point description

Blood samples were collected for serum balstilimab ADA determination.

End point type

Secondary

End point timeframe

Pre-dose through 3 months after last dose

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the number of participants is reported for the participants in Phase 1.

End point values	Phase 1: Dose 1	Phase 1: Dose 2	Phase 1: Dose 3	Phase 1: Dose 4	Phase 1: Dose 5
Number of subjects analysed	10 ^[21]	10 ^[22]	10 ^[23]	10 ^[24]	10 ^[25]
Units: Participant	2	0	0	0	0

Notes
[21] - Safety Analysis Set
[22] - Safety Analysis Set
[23] - Safety Analysis Set
[24] - Safety Analysis Set
[25] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Phase 2: Number of Participants Experiencing TEAEs

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End point title

Phase 2: Number of Participants Experiencing TEAEs ^[26]

End point description

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which did not necessarily have a causal relationship with the treatment. TEAEs were AEs with onset dates during the on-treatment period, or the worsening of an event during the on-treatment period.

End point type

Secondary

End point timeframe

From the time of the first dose to the end of follow-up (up to 2 years after the last dose)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the number of participants is reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	161 ^[27]
Units: Participant	161

Notes
[27] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Phase 2: Maximum Drug Concentration Observed Postdose (Cmax)

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End point title

Phase 2: Maximum Drug Concentration Observed Postdose (Cmax) ^[28]

End point description

Blood samples were collected for serum balstilimab concentration determinations. Results are reported in μg/mL.

End point type

Secondary

End point timeframe

Pre-dose through 3 months after last dose

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the geometric mean and coefficient of variation are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	124 ^[29]
Units: μg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	55.4 ( 42.8 )
Cycle 2 Day 1	56.6 ( 23.9 )

Notes
[29] - Cycle 1 Day 1 (N=124); Cycle 2 Day 1 (N=28)

No statistical analyses for this end point

Secondary: Phase 2: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last)

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End point title

Phase 2: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last) ^[30]

End point description

Blood samples were collected for serum balstilimab concentration determinations. Results are reported in day*μg/mL.

End point type

Secondary

End point timeframe

Pre-dose through 3 months after last dose

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the geometric mean and coefficient of variation are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	124 ^[31]
Units: day*μg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	174 ( 46.3 )
Cycle 2 Day 1	184 ( 59.7 )

Notes
[31] - Cycle 1 Day 1 (N=124); Cycle 2 Day 1 (N=28)

No statistical analyses for this end point

Secondary: Phase 2: Number of Participants with Serum ADAs for Balstilimab

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End point title

Phase 2: Number of Participants with Serum ADAs for Balstilimab ^[32]

End point description

Blood samples were collected for serum balstilimab ADA determination.

End point type

Secondary

End point timeframe

Pre-dose through 3 months after last dose

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the number of participants is reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	161 ^[33]
Units: Participant	8

Notes
[33] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Phase 2: ORR

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End point title

Phase 2: ORR ^[34]

End point description

ORR was defined as proportion of participants with a BOR of CR or PR, as determined by an IERC per RECIST 1.1.

End point type

Secondary

End point timeframe

Up to 4 years

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only percentage and confidence interval are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	160 ^[35]
Units: Percentage of participants
number (confidence interval 95%)	14.4 (9.8 to 20.6)

Notes
[35] - ITT EAS

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DOR)

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End point title

Phase 2: Duration of Response (DOR) ^[36]

End point description

DOR was defined as time from first observation of response to first observation of documented disease progression (or death within 12 weeks after last tumour assessment), per RECIST 1.1 and as determined by an IERC and the investigator. Participants without an event at analysis cutoff date were censored on date of last tumour assessment. Percentile (25th) is reported with 95% confidence interval.

End point type

Secondary

End point timeframe

Up to 4 years

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the 25th percentile and confidence interval are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	160 ^[37]
Units: Month
number (confidence interval 95%)	6.9 (2.8 to 11.0)

Notes
[37] - ITT EAS

No statistical analyses for this end point

Secondary: Phase 2: Disease Control Rate (DCR)

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End point title

Phase 2: Disease Control Rate (DCR) ^[38]

End point description

DCR was defined as the proportion of participants with CR, PR, or stable disease (SD) for at least 12 weeks.

End point type

Secondary

End point timeframe

Up to 4 years

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only percentage and confidence interval are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	160 ^[39]
Units: Percentage of participants
number (confidence interval 95%)	50.6 (43.0 to 58.3)

Notes
[39] - ITT EAS

No statistical analyses for this end point

Secondary: Phase 2: Tumour Control Rate (TCR)

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End point title

Phase 2: Tumour Control Rate (TCR) ^[40]

End point description

TCR was defined as proportion of participants who had a BOR of either SD or a confirmed objective response (CR or PR).

End point type

Secondary

End point timeframe

Up to 2 years

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only percentage and confidence interval are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	160 ^[41]
Units: Percentage of participants
number (confidence interval 95%)	52.5 (44.8 to 60.1)

Notes
[41] - ITT EAS

No statistical analyses for this end point

Secondary: Phase 2: Time to Response (TTR)

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End point title

Phase 2: Time to Response (TTR) ^[42]

End point description

TTR was defined as the time from the first dose date to first observation of confirmed response.

End point type

Secondary

End point timeframe

Up to 4 years

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the mean and standard deviation are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	25 ^[43]
Units: Day
arithmetic mean (standard deviation)	84.4 ( 58.03 )

Notes
[43] - ITT EAS

No statistical analyses for this end point

Secondary: Phase 2: Progression-free Survival (PFS)

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End point title

Phase 2: Progression-free Survival (PFS) ^[44]

End point description

PFS was defined as time from first treatment administration to first observation of documented disease progression (or death within 12 weeks after last tumour assessment), per RECIST 1.1, as determined by an IERC and investigator. Participants without an event at analysis cutoff date were censored on date of last tumour assessment.

End point type

Secondary

End point timeframe

Up to 4 years

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the median and confidence interval are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	160 ^[45]
Units: Month
median (confidence interval 95%)	2.8 (2.4 to 3.9)

Notes
[45] - ITT EAS

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[46]

End point description

OS was defined as time from start of treatment to death. For participants who were still alive at the time of data cutoff for trial analysis or who were lost to follow-up, survival was censored at the last recorded date that the participant was known to have been alive as of the cutoff date for analysis.

End point type

Secondary

End point timeframe

Up to 4 years

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the median and confidence interval are reported for the participants in Phase 2.

End point values	Phase 2: Recommended Phase 2 Dose
Number of subjects analysed	161 ^[47]
Units: Month
median (confidence interval 95%)	11.2 (9.6 to 14.6)

Notes
[47] - Safety Analysis Set

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

4 years

Adverse event reporting additional description

Phase 1 Non-serious Adverse Events: The number '0' is used strictly as a placeholder as the comprehensive Phase 1 data for non-serious adverse events are currently unavailable. The Phase 1 non-serious adverse events will be updated accordingly as soon as the data become available.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Phase 1: Dose 1

Reporting group description

Participants received 1 milligram/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 2

Reporting group description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 3

Reporting group description

Participants received 6 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 4

Reporting group description

Participants received 10 milligrams/kilogram every 2 weeks balstilimab for up to 24 months.

Reporting group title

Phase 1: Dose 5

Reporting group description

Participants received 10 milligrams/kilogram every 3 weeks balstilimab for up to 24 months.

Reporting group title

Phase 2: Recommended Phase 2 Dose

Reporting group description

Participants received 3 milligrams/kilogram every 2 weeks balstilimab for a maximum of 24 months or until progression, unacceptable toxicity, stopping the study drug, or withdrawal from the study.

Serious adverse events	Phase 1: Dose 1	Phase 1: Dose 2	Phase 1: Dose 3	Phase 1: Dose 4	Phase 1: Dose 5	Phase 2: Recommended Phase 2 Dose
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 10 (50.00%)	3 / 10 (30.00%)	5 / 10 (50.00%)	3 / 10 (30.00%)	2 / 10 (20.00%)	90 / 161 (55.90%)
number of deaths (all causes)	1	1	0	0	0	15
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to spine
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	5 / 161 (3.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant ascites
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
General physical health deterioration
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	4 / 161 (2.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed ^[1]	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed ^[2]	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Cervix haemorrhage uterine
subjects affected / exposed ^[3]	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Dyspnoea
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Aortic injury
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis radiation
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiopulmonary failure
subjects affected / exposed	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ischaemic stroke
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic fistula
subjects affected / exposed	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper GI haemorrhage
subjects affected / exposed	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	7 / 161 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated enterocolitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	5 / 161 (3.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Biliary dilatation
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Psoriasis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	6 / 161 (3.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Renal failure
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated nephritis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postrenal failure
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelocaliectasis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oliguria
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urogenital fistula
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impetigo
subjects affected / exposed	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 161 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Corona virus infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	4 / 161 (2.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 161 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arboviral infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia pyelonephritis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 161 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 161 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This serious adverse event only affected female participants.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This serious adverse event only affected female participants.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This serious adverse event only affected female participants.

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1: Dose 1	Phase 1: Dose 2	Phase 1: Dose 3	Phase 1: Dose 4	Phase 1: Dose 5	Phase 2: Recommended Phase 2 Dose
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	160 / 161 (99.38%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	9 / 161 (5.59%)
occurrences all number	0	0	0	0	0	11
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	56 / 161 (34.78%)
occurrences all number	0	0	0	0	0	105
Fatigue
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	37 / 161 (22.98%)
occurrences all number	0	0	0	0	0	70
Pyrexia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	35 / 161 (21.74%)
occurrences all number	0	0	0	0	0	48
Oedema peripheral
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	21 / 161 (13.04%)
occurrences all number	0	0	0	0	0	28
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed ^[4]	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	25 / 161 (15.53%)
occurrences all number	0	0	0	0	0	30
Vaginal haemorrhage
subjects affected / exposed ^[5]	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	16 / 161 (9.94%)
occurrences all number	0	0	0	0	0	19
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	31 / 161 (19.25%)
occurrences all number	0	0	0	0	0	38
Dyspnoea
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	23 / 161 (14.29%)
occurrences all number	0	0	0	0	0	27
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	16 / 161 (9.94%)
occurrences all number	0	0	0	0	0	18
Insomnia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	15 / 161 (9.32%)
occurrences all number	0	0	0	0	0	17
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	17 / 161 (10.56%)
occurrences all number	0	0	0	0	0	30
Alanine aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	17 / 161 (10.56%)
occurrences all number	0	0	0	0	0	26
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	17 / 161 (10.56%)
occurrences all number	0	0	0	0	0	22
Aspartate aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	16 / 161 (9.94%)
occurrences all number	0	0	0	0	0	29
Weight decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	16 / 161 (9.94%)
occurrences all number	0	0	0	0	0	18
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	13 / 161 (8.07%)
occurrences all number	0	0	0	0	0	19
Lipase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	9 / 161 (5.59%)
occurrences all number	0	0	0	0	0	12
Nervous system disorders
Headache
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	26 / 161 (16.15%)
occurrences all number	0	0	0	0	0	35
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	80 / 161 (49.69%)
occurrences all number	0	0	0	0	0	230
Lymphopenia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	13 / 161 (8.07%)
occurrences all number	0	0	0	0	0	23
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	47 / 161 (29.19%)
occurrences all number	0	0	0	0	0	65
Constipation
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	45 / 161 (27.95%)
occurrences all number	0	0	0	0	0	63
Diarrhoea
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	41 / 161 (25.47%)
occurrences all number	0	0	0	0	0	66
Vomiting
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	38 / 161 (23.60%)
occurrences all number	0	0	0	0	0	50
Abdominal pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	35 / 161 (21.74%)
occurrences all number	0	0	0	0	0	57
Abdominal pain upper
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	11 / 161 (6.83%)
occurrences all number	0	0	0	0	0	13
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	30 / 161 (18.63%)
occurrences all number	0	0	0	0	0	46
Rash
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	10 / 161 (6.21%)
occurrences all number	0	0	0	0	0	11
Dry skin
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	9 / 161 (5.59%)
occurrences all number	0	0	0	0	0	14
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	10 / 161 (6.21%)
occurrences all number	0	0	0	0	0	11
Proteinuria
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	9 / 161 (5.59%)
occurrences all number	0	0	0	0	0	16
Haematuria
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	9 / 161 (5.59%)
occurrences all number	0	0	0	0	0	11
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	11 / 161 (6.83%)
occurrences all number	0	0	0	0	0	12
Immune-mediated hypothyroidism
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	9 / 161 (5.59%)
occurrences all number	0	0	0	0	0	13
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	36 / 161 (22.36%)
occurrences all number	0	0	0	0	0	48
Arthralgia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	22 / 161 (13.66%)
occurrences all number	0	0	0	0	0	32
Pain in extremity
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	19 / 161 (11.80%)
occurrences all number	0	0	0	0	0	22
Myalgia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	14 / 161 (8.70%)
occurrences all number	0	0	0	0	0	16
Muscle spasms
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	12 / 161 (7.45%)
occurrences all number	0	0	0	0	0	21
Musculoskeletal pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	9 / 161 (5.59%)
occurrences all number	0	0	0	0	0	10
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	35 / 161 (21.74%)
occurrences all number	0	0	0	0	0	52
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	34 / 161 (21.12%)
occurrences all number	0	0	0	0	0	40
Hyponatraemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	19 / 161 (11.80%)
occurrences all number	0	0	0	0	0	34
Hyperglycaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	15 / 161 (9.32%)
occurrences all number	0	0	0	0	0	15
Hypomagnesaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	13 / 161 (8.07%)
occurrences all number	0	0	0	0	0	16
Hypokalaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	10 / 161 (6.21%)
occurrences all number	0	0	0	0	0	19

Notes
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This non-serious adverse event only affected female participants.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This non-serious adverse event only affected female participants.

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Were there any global substantial amendments to the protocol? Yes

26 Sep 2017

- Addition of an expansion cohort in which approximately 40 participants with American Joint Committee on Cancer Stage IV cutaneous squamous cell carcinoma (cSCC) not curable by radiation therapy were to be enrolled. - Addition of an IDMC to monitor the cervical cancer and cSCC expansion cohorts. - Addition of a futility analysis (at >50% information fraction) to expansion cohorts in response to the request from Institutional Review Boards for futility analysis for cervical cancer cohort. - Removed assessment of immune-related RECIST as secondary endpoint. Assessment of tumour response was according to RECIST 1.1. - Removed continuation of treatment after a relapse following CR. - Requirement that participants enrolled in Phase 2 need to provide archival tumour tissue sample. - Added allowance for treatment beyond disease progression. - Added criteria for treatment delay and criteria to resume treatment. - Added specification for palliative radiation therapy as permitted for a single lesion provided it is not to a target lesion and treatment was not administered for tumour control.

24 Jan 2019

- Removed the Phase 2 expansion cohort for cSCC. This cohort was removed based on a company strategic decision to focus on the indication of cervical cancer based on the experience in the escalation phase data to date. No participants with cSCC were enrolled. - Reorganized and refined the study objectives and endpoints for Phase 1 versus Phase 2, to (1) be consistent with terminology and definitions for endpoints (for example best overall response versus objective response rate) based on Food and Drug Administration (FDA) guidelines, (2) clearly identify the objectives for Phase 1 versus Phase 2 of the study, and (3) clearly show which endpoints are associated with each objective. - Removed the futility analysis for efficacy endpoints in Phase 2 expansion cohorts. This change was made because the Phase 2 portion of the study was to include a full interim analysis by an IDMC to assess all available data and make a recommendation to the Sponsor, instead of having just a predefined study stop cut-off. - Added expanded electrocardiogram evaluation in Phase 2. This change was made in alignment with PK timepoints to enable an assessment of the effects of study drug on cardiac conduction. - Changed Study Title from “Expansion to Select Solid Tumors” to “Expansion to Cervical Cancer”. - Changed dose delay interval that resulted in treatment withdraw from more than 10 weeks to more than 6 weeks. - Changed timing of initial tumour imaging from within 18 days before first dose to within 21 days. - Added tumour PD-L1 expression was to be assessed using an FDA-approved test.

27 Sep 2019

- Phase 2 population increase, and post-interim analysis enrollment language clarified. - Statistical calculation changes based on population increase. - Clinical progression criteria defined to accommodate absence of radiologic progression on basis of RECIST 1.1.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Comprehensive Phase 1 data for subject disposition and non-serious adverse events are currently unavailable. Both will be updated accordingly as soon as the data become available.

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Clinical trials

Clinical Trial Results: A Phase 1/2, Open-Label, Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Patients With Metastatic or Locally Advanced Solid Tumors, With Expansion to Second-Line Cervical Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Number of Participants Experiencing DLTs for Balstilimab

Primary: Phase 1: Number of Participants Experiencing DLTs for Balstilimab

Primary: Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 2: Objective Response Rate (ORR)

Primary: Phase 2: Objective Response Rate (ORR)

Secondary: Phase 1: Receptor Occupancy of Circulating T Cells

Secondary: Phase 1: Receptor Occupancy of Circulating T Cells

Secondary: Phase 1: Maximum Drug Concentration Observed Postdose (Cmax)

Secondary: Phase 1: Maximum Drug Concentration Observed Postdose (Cmax)

Secondary: Phase 1: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last)

Secondary: Phase 1: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last)

Secondary: Part 1: Number of Participants with Serum Anti-drug Antibodies (ADAs) for Balstilimab

Secondary: Part 1: Number of Participants with Serum Anti-drug Antibodies (ADAs) for Balstilimab

Secondary: Phase 2: Number of Participants Experiencing TEAEs

Secondary: Phase 2: Number of Participants Experiencing TEAEs

Secondary: Phase 2: Maximum Drug Concentration Observed Postdose (Cmax)

Secondary: Phase 2: Maximum Drug Concentration Observed Postdose (Cmax)

Secondary: Phase 2: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last)

Secondary: Phase 2: Area Under the Drug Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC0-last)

Secondary: Phase 2: Number of Participants with Serum ADAs for Balstilimab

Secondary: Phase 2: Number of Participants with Serum ADAs for Balstilimab

Secondary: Phase 2: ORR

Secondary: Phase 2: ORR

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 2: Disease Control Rate (DCR)

Secondary: Phase 2: Disease Control Rate (DCR)

Secondary: Phase 2: Tumour Control Rate (TCR)

Secondary: Phase 2: Tumour Control Rate (TCR)

Secondary: Phase 2: Time to Response (TTR)

Secondary: Phase 2: Time to Response (TTR)

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1/2, Open-Label, Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Patients With Metastatic or Locally Advanced Solid Tumors, With Expansion to Second-Line Cervical Cancer